Folinic acid (also known as Leucovorin or Citrovorum factor) is an N-substituted derivative of L-glutamic acid bearing the chemical designation, N-[4[2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amin o]benzoyl]-L-glutamic acid or 5-formyl tetrahydrofolic acid. Folinic acid has two chiral centers; one at the .alpha.-position of its glutamic acid group, and, the other at the C-6 carbon atom of its tetrahydropteroyl ring. Folinic acid differs in configuration at only one of these chiral centers because the glutamic acid group is derived exclusively from the L-form of this substituent. When prepared chemically using a reducing agent such as diethylamine borane [Forsch, R. A., Rosowsky, A., J. Org. Chem. 50, 2582-2583 (1985)], folinic acid consists of a 1:1 mixture of 6R and 6S forms. However, when isolated from biological sources folinic acid occurs only in the (6S)-form and, generally, contains 1 to 15 additional .gamma.-linked L-glutamic acid residues.
A number of reports [Kalman, T. I., Chem. Biol. Pteridines, Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects, 8th, 1986, 763-766, Edited by Cooper, B. A., Whitehead, V. M., de Gruyter, Berlin, Fed. Rep. Ger.; Schirch, V. et al., ibid, 887-898; Mackenzie, R. E., Baugh, C. M., Adv. Exp. Med. Biol., 163: Folyl and Anti-Folyl Polyglutamates, 1983, 19-34, Edited by Goldman, I. D., Chabner, B. A., Bertino, J. R., Plenum Press, New York, U.S.A.; Baggott, J. E., Krumdieck, C. L., Chem. Biol. Pteridines: Dev. Biochem., 4, 6th, 1978 (Pub. 1979), 347-351, Edited by Kisliuk, R. L., Brown, G. M., Elsevier/North-Holland, New York, U.S.A.] indicate that tetrahydropteroylpoly-L-glutamic acid derivatives have greatly enhanced substrate and/or inhibitor activity when assayed against several folic acid enzymes compared with the mono-L-glutamic acid forms. The availability of these derivatives has been limited by the difficulty encountered in producing large quantities of the (6S)-form of tetrahydrofolic acid [Rees, L. et al., Tetrahedron, 42, 117-136 (1986)]. Until now no direct purely chemical method existed for converting tetrahydropteroylmono-L-glutamic acid derivatives to their poly-L-glutamic acid forms.